The present invention relates to indolylmaleimide derivatives, process for their production and pharmaceutical compositions containing them.
More particularly the present invention provides a compound of formula I 
wherein
Ra is H; C1-4alkyl; or C1-4alkyl substituted by OH, NH2, NHC1-4alkyl or N(C1-4alkyl)2;
Rb is H; or C1-4alkyl;
R is a radical of formula (a), (b), (c), (d), (e) or (f) 
xe2x80x83wherein
each of R1, R4, R7, R8, R11 and R14 is OH; SH; a heterocyclic residue; NR16R17 wherein each of R16 and R17, independently, is H or C1-4alkyl or R16 and R17form together with the nitrogen atom to which they are bound a heterocyclic residue; or a radical of formula xcex1
xe2x80x94Xxe2x80x94Rcxe2x80x94Yxe2x80x83xe2x80x83(xcex1)
wherein X is a direct bond, O, S or NR18 wherein R18 is H or C1-4alkyl,
Rc is C1-4alkylene or C1-4alkylene wherein one CH2 is replaced by CRxRy wherein one of Rx and Ry is H and the other is CH3, each of Rx and Ry is CH3 or Rx and Ry form together xe2x80x94CH2xe2x80x94CH2xe2x80x94, and
Y is bound to the terminal carbon atom and is selected from OH, a heterocyclic residue and xe2x80x94NR19R20 wherein each of R19 and R20 independently is H, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, aryl-C1-4alkyl or C1-4alkyl optionally substituted on the terminal carbon atom by OH, or R19 and R20 form together with the nitrogen atom to which they are bound a heterocyclic residue;
each of R2, R3, R5, R6, R9, R10, R12, R13, R15 and Rxe2x80x215, independently, is H, halogen, C1-4alkyl, CF3, OH, SH, NH2, C1-4alkoxy, C1-4alkylthio, NHC1-4alkyl, N(C1-4alkyl)2 or CN;
either E is xe2x80x94Nxe2x95x90 and G is xe2x80x94CHxe2x95x90 or E is xe2x80x94CHxe2x95x90 and G is xe2x80x94Nxe2x95x90; and
ring A is optionally substituted.
Any alkyl or alkyl moiety in e.g. alkoxy may be linear or branched. Halogen may be F, Cl, Br or I, preferably F or Cl. Any aryl may be phenyl or naphthyl, preferably phenyl.
By heterocyclic residue as R1, R4, R7, R8, R11, R14 or Y or formed, respectively, by NR16R17 or NR19R20, is meant a three to eight, preferably five to eight, membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S, and optionally substituted. Suitable examples include e.g. pyridyl, e.g. 3- or 4-pyridyl, piperidyl, e.g. piperidin-1-yl, 3- or 4-piperidyl, homopiperidyl, piperazinyl, homopiperazinyl, morpholin-4-yl, imidazolyl, imidazolidinyl, pyrrolyl or pyrrolidinyl, optionally substituted, e.g. mono- or polysubstituted. When the heterocyclic residue is substituted, this may be on one or more ring carbon atoms and/or on a ring nitrogen atom when present. Examples of a substituent on a ring carbon atom include e.g. C1-4alkyl e.g. CH3;
C3-6cycloalkyl e.g. cyclopropyl, optionally further substituted by C1-4alkyl; 
xe2x80x83wherein p is 1,2 or 3, preferably 1; CF3; halogen; OH; NH2; xe2x80x94CH2xe2x80x94NH2; xe2x80x94CH2xe2x80x94OH; piperidin-1-yl; pyrrolidinyl. Examples of a substituent on a ring nitrogen atom are e.g. C1-6alkyl; acyl, e.g. Rxe2x80x2x-CO wherein Rxe2x80x2x is H, C1alkyl or phenyl optionally substituted by C1-4alkyl, C1-4alkoxy or amino, e.g formyl; C3-6cycloalkyl; C3-6cycloalkylxe2x80x94C1-4alkyl; phenyl; phenyl-C1-4alkyl e.g. benzyl; a heterocyclic residue, e.g. as disclosed above, e.g. an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms; or a residue of formula xcex2
xe2x80x94R21xe2x80x94Yxe2x80x2xe2x80x83xe2x80x83(xcex2)
wherein R21 is C1-4alkylene or C2-4alkylene interrupted by O and Yxe2x80x2 is OH, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2.
C2-4alkylene interrupted by O may be e.g. xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94.
When the substituent on a cyclic nitrogen is a heterocyclic residue, it may be a five or six membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S. Examples include e.g. 3- or 4-pyridyl, piperidyl, e.g. piperidin-1-yl, 3- or 4-piperidyl, homopiperidyl, piperazinyl, homopiperazinyl, pyrimidinyl, morpholin-4-yl, imidazolyl, imidazolidinyl, pyrrolyl or pyrrolidinyl,
When Ra is substituted C1-4alkyl, the substituent is preferably on the terminal carbon atom.
When ring A is substituted, it may be mono- or polysubstituted, preferably monosubstituted, the substituent(s) being selected from the group consisting of e.g. halogen, OH, C1-4alkoxy, e.g. OCH3, C1-4alkyl, e.g. CH3, NO2, CF3, NH2, NHC1-4alkyl, N(C1-4alkyl)2 and CN. For example, ring A may be a residue of formula 
wherein
Rd is H; C1-4alkyl; or halogen; and
Re is OH; NO2; NH2; NHC1-4alkyl; or N(C1-4alkyl)2.
When Ra has a CH2 replaced by CRxRY, it is preferably the CH2 bearing Y.
Examples of heterocyclic residue as R1, R4, R7, R8, R11, R14 or Y or formed, respectively, by NR16R17 or NR19R20, include e.g. a residue of formula (xcex3) 
wherein
the ring D is a 5, 6 or 7 membered saturated, unsaturated or aromatic ring;
Xb is xe2x80x94Nxe2x80x94, xe2x80x94Cxe2x95x90 or xe2x80x94CHxe2x80x94;
Xc is xe2x80x94Nxe2x95x90, xe2x80x94NRfxe2x80x94, xe2x80x94CRfxe2x80x2xe2x80x94 or xe2x80x94CHRfxe2x80x2xe2x80x94 wherein Rf is a substituent as indicated above for a ring nitrogen atom, and Rfxe2x80x2 is a substituent as indicated above for a ring carbon atom;
the bond between C1 and C2 is either saturated or unsaturated;
each of C1 and C2, independently, is a carbon atom which is optionally substituted by one or two substituents selected among those indicated above for a ring carbon atom; and
the line between C3 and Xb and between C1 and Xb, respectively, represents the number of carbon atoms as required to obtain a 5, 6 or 7 membered ring D.
A preferred residue of formula (xcex3) is one wherein the ring D forms a 1,4-piperazinyl ring optionally C- and/or N-substituted as indicated.
Representative examples of a residue of formula (xcex3) are e.g. 3- or 4- pyridyl; piperidin-1-yl; 1-N-(C1-4alkyl)- or xe2x80x94(xcfx89-hydroxyxe2x80x94C1-4alkyl)-3-piperidyl; morpholin-4-yl; imidazolyl; pyrrolidinyl; 1-piperazinyl; 2-C1-4alkyl- or -C3-6cycloalkyl-1-piperazinyl; 3-C1-4alkyl- or xe2x80x94C3-6cycloalkyl-1-piperazinyl; 2,2- or 3,5- or 2,5- or 2,6-di(C1-4alkyl)-1-piperazinyl; 3,4,5-tri-(C1-4alkyl)-1-piperazinyl; 4-N-(C1-4alkyl)- or xe2x80x94(xcfx89-hydroxy-C1-4alkyl)- or xe2x80x94(xcfx89-dimethylamino-C1-4alkyl)-1-piperazinyl; 4-N-pyridin-4-yl-1-piperazinyl; 4-N-phenyl- or xe2x80x94C3-6cycloalkyl-1-piperazinyl; 4-N-(C1-4alkyl)- or xe2x80x94(xcfx89-hydroxy-C1-4alkyl)-3-C1-4alkyl- or xe2x80x943,3-di(C1-4alkyl)-1-piperazinyl; 4-N-(1-C1-4alkyl-C3-6cycloalkyl)-1-piperazinyl; 4-N-formyl-1-piperazinyl; 4-N-pyrimidin-2-yl-1-piperazinyl; or 4-N-C1-4alkyl-1-homopiperazinyl.
The compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. organic or inorganic acids, for example, hydrochloric acid, acetic acid, when R1, R4, R7, R8, R11 or R14 and/or R2, R3, R5, R6, R9, R10, R12, R13 or R15 comprises an optionally substituted amino group or a heterocyclic residue which can form acid addition salts.
It will be appreciated that the compounds of formula I may exist in the form of optical isomers, racemates or diastereoisomers. For example, a ring carbon atom bearing a substituent in the heterocyclic residue as R1, R4, R7, R8, R11, R14 or Y or formed, respectively, by NR16R17 or NR19R20, is asymmetric and may have the D- or L- configuration. It is to be understood that the present invention embraces all enantiomers and their mixtures. Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms as mentioned.
In the compounds of formula I, the following significances are preferred individually or in any sub-combination:
1. Ra is H or CH3;
2. Rb is H;
3. Ring A is unsubstituted; or is substituted by methyl in position 7;
4. Preferred heterocyclic residue as formed by NR16R17 is e.g. piperazin-1-yl optionally N-substituted, e.g. by C1-4aakyl, xcfx89-hydroxy-C1-4alkyl, xcfx89-dimethylamino-C1-4alkyl, C5-6cycloalkyl, C1-4alkyl-C5-6cycloalkyl, an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms, e.g. pyridyl or pyrimidin-2-yl, or aresidue of formula xcex2 as defined above and/or optionally C-substituted, e.g. by CH3 e.g. in positions 2, and/or 3 and/or 5 and/or 6 and/or 2,2 or 3,3 or by 
xe2x80x83e.g. in position 2 or 3; piperidin-1-yl optionally C-substituted, e.g. in position 4, by NH2, xe2x80x94CH2xe2x80x94NH2 or piperidin-1-yl, or in position 3, e.g. by OH or NH2; or pyrrolidinyl optionally C-substituted in position 3 by OH or NH2;
5. R18 is H or CH3;
6. Rc is C1-4alkylene or C1-4alkylene wherein the terminal CH2 is replaced by CRxRy wherein Rx and Ry form together xe2x80x94CH2xe2x80x94CH2xe2x80x94;
7. X is O;
8. The radical of formula (xcex1) is xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Y;
9. Each of R19 and R20 is H, C1-4alkyl, e.g. methyl, C1-4alkyl substituted on the terminal carbon atom by OH, e.g. xe2x80x94CH2xe2x80x94CH2xe2x80x94OH, or cyclopropyl;
10. Preferred heterocyclic residue as formed by NR19R20 is e.g. piperazin-1-yl optionally N-substituted by C1-4alkyl or a residue of formula xcex2; piperidin-1-yl; 1-(C1-4alkyl)-piperidin-3-yl; 3- or 4-pyridyl; imidazolyl; pyrrolidinyl; or morpholin-4-yl;
11. Each of R1, R4, R7, R8, R11 or R14, independently, is 1-N-methyl-piperidin-4-yl; 4-methyl-piperazin-1-yl; 4-methyl-1-homopiperazinyl; 4-(2-hydroxyethyl)-piperazin-1-yl; or xe2x80x94Xxe2x80x2xe2x80x94C1,2 or 3-alkylene-NR19R20 wherein Xxe2x80x2 is a direct bond, O or NH;
12. In the residue of formula (a) either each of R2 and R3 is H or one of R2 and R3 is H and the other is F, Cl, CH3, OH, OCH3 or CF3;
13. In the residue of formula (a) R2 is OH;
14. In the residue of formula (b) either each of R5 and R6 is H or one of R5 and R6 is H and the other is F, Cl, CH3, OCH3 or CF3;
15. In the residue of formula (b) R4 is a radical of formula (xcex1) or NR16R17;
16. In the residue of formula (d) either each of R9 and R10 is H or one of R9 and R10 is H and the other is F, Cl, CH3, OCH3 or CF3; preferably R10 is H and R9 is in position 5, 6, 7 or 8, preferably in position 6;
17. In the residue of formula (e) each of R12 and R13 is H;
18. In the residue of formula (e) one of R12 and R13 is H and the other is F, Cl, CH3, OCH3 or CF3;
when E is xe2x80x94Nxe2x95x90 and G is xe2x80x94CHxe2x95x90, preferably R13 is H and R12 is in position 6 or 7;
when E is xe2x80x94CHxe2x95x90 and G is xe2x80x94Nxe2x95x90, preferably R13 is H and R12 is in position 7;
19. In the residue of formula (f) R15 is H, CH3 or Cl, e.g. in position 5 or 6;
20. In the residue of formula (f) Rxe2x80x215 is H or CH3, e.g. in position 5, preferably H;
21. R is a radical of formula (d), (e) or (f).
The present invention also includes a process for the preparation of a compound of formula I which process comprises
a) reacting a compound of formula II 
wherein Ra, Rb and ring A are as defined above, with a compound of formula III
Rxe2x80x94CH2xe2x80x94COxe2x80x94NH2xe2x80x83xe2x80x83(III)
wherein R is as defined above,
b) reacting a compound of formula IV 
wherein Ra, Rb and ring A are as defined above, with a compound of formula V
Rxe2x80x94COxe2x80x94COxe2x80x94OCH3xe2x80x83xe2x80x83(V)
wherein R is as defined above; or
c) converting in a compound of formula I a substituent R1, R4, R7, R8, R11 or R14 into another substituent R1, R4, R7, R8, R11 or R14 
and, where required, converting the resulting compound of formula I obtained in free form to a salt form or vice versa, as appropriate.
Process steps a) and (b) may conveniently be effected in the presence of a strong base, e.g. t-BuOK. When compounds of formula III or V comprising an OH group which should not participate to the reaction are used, such OH group is in protected form. The OH-protecting group may be removed according to methods known in the art at the end of condensation step a) or b). Process step c) may be carried out according to known methods: for example when R1, R4, R7, R8, R11, or R14 comprises a final OH group, this OH group may be replaced by the desired xe2x80x94NR16R17 or xe2x80x94NR19R20.
Compounds of formula II may be prepared by reacting the corresponding indol compound with an oxalyl halogenide, e.g. chloride, or with a monoalkyl oxalyl chloride under basic conditions, e.g. as disclosed in Example 28.
Compounds of formula III or V, used as starting materials, may be prepared in accordance with known methods, e.g. by introducing the desired substituent R1, R4, R7, R8, R11 or R14, respectively, in a compound of formula IIIxe2x80x2 or Vxe2x80x2
Rxe2x80x2xe2x80x94CH2xe2x80x94COxe2x80x94NH2xe2x80x83xe2x80x83(IIIxe2x80x2)
Rxe2x80x3xe2x80x94COxe2x80x94COxe2x80x94OCH3xe2x80x83xe2x80x83(Vxe2x80x2)
wherein each of Rxe2x80x2 or Rxe2x80x3 is respectively a radical of formula (a), (b), (c), (d), (e) or (f), each of which comprising a leaving group, e.g. halogen, in place of R1, R4, R7, R8, R11, or R14. 
Alternatively, compounds of formula III wherein R is a radical of formula (a), (b) or (c), R1, R4 or R7 being a radical of formula (xcex1), may be prepared in accordance with known methods by reacting a compound of formula IIIxe2x80x2 wherein Rxe2x80x2 is respectively a radical of formula (a), (b) or (c), each of which comprising OH in place of R1, R4or R7, with a compound of formula Xaxe2x80x94Xxe2x80x94Rcxe2x80x94Y wherein Xa is a leaving group, e.g. Cl, and X, Rc or Y are as defined above.
Compounds of formula I wherein R is a radical of formula (e) wherein E is xe2x80x94Nxe2x95x90, G is xe2x80x94CHxe2x95x90 and R11 is xe2x80x94Oxe2x80x94Rcxe2x80x94Y or xe2x80x94Sxe2x80x94Rcxe2x80x94Y may also be prepared by reacting together a compound of formula II as defined above with a compound of formula IIIxe2x80x2 wherein Rxe2x80x2 is a radical of formula (exe2x80x2) 
wherein R12 and R13 are as defined above and Xa is a leaving group, e.g. halogen, and with a compound of formula VI
Rxe2x80x211Hxe2x80x83xe2x80x83(VI)
wherein Rxe2x80x211 is xe2x80x94Oxe2x80x94Rcxe2x80x94Y or xe2x80x94Sxe2x80x94Rcxe2x80x94Y. This reaction may be carried out in accordance with know methods, e.g. as disclosed in Example 28 below.
Compounds of formula I wherein R is a radical of formula (d) or (f) wherein R8 or R14 is xe2x80x94Oxe2x80x94Rcxe2x80x94Y or xe2x80x94Sxe2x80x94Rcxe2x80x94Y may also be prepared by reacting together a compound of formula II as defined above with a compound of formula IIIxe2x80x2 wherein Rxe2x80x3 is a radical of formula (dxe2x80x2) or (fxe2x80x2) 
wherein R9, R10, R15 and Rxe2x80x215 are as defined above and Xa is a leaving group, e.g. halogen, and with a compound of formula VIxe2x80x2
Axe2x80x94Hxe2x80x83xe2x80x83(VI)
wherein A is xe2x80x94Oxe2x80x94Rcxe2x80x94Y or xe2x80x94Sxe2x80x94Rcxe2x80x94Y. This reaction may be carried out in accordance with know methods.
Insofar as the production of the starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as described hereafter.